9-Oxobenzomorphan process

ABSTRACT

Improved processes for preparing 2&#39;-alkoxy-2,5-di-substituted-9-oxo-6,7-benzomorphans from benz[e]indolines and synthesis of the benz[e]indoline intermediates are described. A representative example involves synthesis of 9b-allyl-8-methoxy-3-methyl-5,9b-dihydrobenz[e]indoline and bromination thereof to 9b-allyl-4-bromo-8-methoxy-2,4,5,9b-tetrahydro-1H-benz[e]indole methylbromide which is then hydrolyzed with a weak base such as ammonium bicarbonate to provide 5-allyl-2&#39;-methoxy-2-methyl-9-oxo-6,7-benzomorphan.

CROSS-REFERENCE TO RELATED APPLICATION

This applicaion is a divisional of U.S. patent application Ser. No.870,409 filed Jan. 18, 1978 (now U.S. Pat. No. 4,150,032).

DESCRIPTION OF THE PRIOR ART

(1) Takeda, et al., J. Org. Chem. 37 (17), 2677-2679 (1972) describes animproved synthesis of a 9-oxo-6,7-benzomorphan of formula (5) asoutlined below ##STR1## According to Takeda, et al., thedihydrobenz[e]indoline intermediate (3) was prepared from thenaphthalenone (1) in 48% overall yield and converted to the9-oxobenzomorphan (5) in 60% yield without isolation of the intermediatebromoiminium bromide (4). The 9-oxobenzomorphan (5) was obtained bytreating the bromoiminium bromide (4) with aqueous ammonium hydroxide.According to Takeda, et al., the use of hydroxide is essential to therearrangement of (4) to (5) since substitution of anhydroustriethylamine for aqueous ammonium hydroxide did not give (5).

(2) Monkovic, et al., U.S. Pat. No. 3,891,657 describes an improvedprocess for the preparation of2'-methoxy-2,5-dimethyl-9-oxo-6,7-benzomorphan (4) involving catalyticdebenzylation of methobromide (3) which in turn is obtained byalkylating ketone (1) with 2-benzylmethylaminoethylchloride followed bybromination of the hydrobromide salt of (2) with subsequentneutralization of the brominated material with ammonium hydroxide.##STR2##

(3) Murphy, et al., J. Org. Chem., 25, 1386-1388 (1960) and Ahmed, etal., Can. J. Chem., 53, 3276-3284 (1975) describe the synthesis of2'-methoxy-2,5-dimethyl-9-oxo-6,7-benzomorphan (5) by pyrolysis of thecorresponding methobromide (4) according to the following flow-sheet.The methobromide intermediate (4) was obtained by a multi-step processinvolving dimethylaminoethylation of ketone (1) and bromination of thehydrobromide salt of the alkylated ketone (2) to provide thehydrobromide salt of bromo-ketone (3) which neutralized with ammoniacyclized to the methobromide (4) intermediate. ##STR3##

(4) Monkovic, et al., U.S. Pat. No. 3,853,889 and U.S. Pat. No.3,959,290 and Ahmed, et al., Can. J. Chem., 53, 3276-3284 (1975)describe the synthesis of2'-methoxy-2-methyl-5-allyl-9-oxo-6,7-benzomorphan ##STR4## according tothe procedure described by Murphy, et al., J. Org. Chem., 25, 1386-1388(1960).

(5) French Pat. No. 2,096,914-Q (Derwent Abstracts No. 31347T-B)describes the synthesis of benzoindoles (4) from tetralone startingmaterials (1) according to the following scheme in which substituents R,R¹ and R² are alkyl and Y represents hydrogen, hydroxy and alkoxy.##STR5##

(6) Evans, et al., J. Org. Chem. 35, 4122-4127 (1970) report thesynthesis of 3-methyl-1,2,4,5-tetrahydro-3H-benz[e]indole (1) by twomethods. One method involves treating tetralone enamine (2) first withisopropyl magnesium chloride and then with bromochloroethane. The secondmethod involves hydrolysis of the ketone amine (3). ##STR6##

SUMMARY OF THE INVENTION

In its broadest aspect, this invention is concerned with a process forpreparing 2'-alkoxy-2,5-di-substituted-9-oxo-6,7-benzomorphans havingformula I ##STR7## in which R₁ is lower alkyl or benzyl;

R₂ is lower alkyl, allyl, benzyl or ##STR8## R₃ is lower alkyl, ##STR9##in which R₄ is hydrogen or methyl.

Such 9-oxo-6,7-benzomorphans are valuable intermediates employed in thepreparation of analgesics, narcotic antagonists and antitussivesdescribed in Monkovic, et al., U.S. Pat. Nos. 3,891,657; 3,853,889;3,959,290; 3,966,747; Montzka, et al., U.S. Pat. No. 3,956,336 andAlbertson, U.S. Pat. No. 4,009,171.

The instant process involves conversion of a benz[e]indoline (e.g.9b-allyl-8-methoxy-3-methyl-5,9b-dihydrobenz[e]indoline) to thecorresponding 9-oxo-6,7-benzomorphan (e.g.5-allyl-2'-methoxy-2-methyl-9-oxo-6,7-benzomorphan) by brominating thedihydrobenz[e]indoline to provide a brommoenaminium bromide intermediatewhich is then hydrolyzed and rearranged with weak bases (e.g. ammoniumbicarbonate or sodium bicarbonate) or activated aluminum oxide.Additional aspects of the invention are concerned with processes for thepreparation of the benz[e]indoline starting materials and novelintermediates therefor.

DETAILED DESCRIPTION OF THE INVENTION

The 2'-alkoxy-2,5-disubstituted-9-oxo-6,7-benzomorphan of the inventionhave the basic 6,7-benzomorphan nucleus illustrated by numbered planarformula I. ##STR10##

Numbered planar formula II depicts the basic nucleus of thebenz[e]indolines employed in preparation of the "6,7-benzomorphan".##STR11##

For the purpose of this disclosure the term "lower alkyl" refers to acarbon chain of 1 to 4 carbon atoms inclusive wherein the carbon chainis comprised of both straight and branched chain carbon radicals.Exemplary of these carbon chain radicals are methyl, ethyl, propyl,isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl and tert.-butyl.

The following chart illustrates the process of the invention forconverting benz[e]indolines of formula II to the formula I9-oxo-6,7-benzomorphans wherein R₁, R₂ and R₃ are as defined above.##STR12##

Examples of 9-oxo-6,7-benzomorphan provided by the above process arethose compounds of formula I wherein R₁, R₂ and R₃ are as defined inTable I below.

                  TABLE I                                                         ______________________________________                                        Formula I Compounds                                                           R.sub.1     R.sub.2          R.sub.3                                          ______________________________________                                        (Ia)  methyl   allyl           methyl                                         (Ib)  methyl   methyl          methyl                                         (Ic)  benzyl   allyl           methyl                                         (Id)  methyl                                                                                  ##STR13##      methyl                                         (Ie)  methyl   allyl                                                                                          ##STR14##                                     (If)  methyl   allyl                                                                                          ##STR15##                                     (Ig)  benzyl   allyl                                                                                          ##STR16##                                     (Ih)  methyl   benzyl          methyl                                         (Ii)  methyl   methyl                                                                                         ##STR17##                                     ______________________________________                                    

In carrying out step 1 of the process outlined in Chart I.benz[e]indolines of Formula II are brominated to provide bromoenaminiumbromides of Formula III. The bromination is preferably carried out byadding a solution of the benz[e]indoline II in methylene chloride to asolution of bromine in the same solvent while maintaining a reactiontemperature in the range of -40° to -70°. The addition of the methylenechloride solution of the benz[e]indoline II is carriedout rapidly byall-at-once mixing in a batchwise fashion. The reverse process wherein amethylene chloride solution of bromine is added batch-wise to a solutionof the formula II benz[e]indoline is also satisfactory and providessimilar yields of III. However, if a methylene chloride solution ofbromine is added drop-wise to a solution of benz[e]indoline II inmethylene chloride, the bromoenaminium bromide III is contaminated withappreciable quantities of the hydrobromide salt of the starting enamineII and the yield is substantially lower. Selection of the reactionsolvent is also critical in step 1 as well as the mode of addition ofthe reactants. For instance, when a solution of bromine in ether isadded gradually to a solution of IIa (R₁ =R₃ =methyl, R₂ =allyl) inmethylene chloride at -60°, the material obtained is mainly thehydrobromide of IIa. Suitable solvents for carrying out step 1 arehalogenated hydrocarbons (e.g., methylene chloride, chloroform andethylene chloride).

The formula III bromoenaminium bromides are converted to the formula I9-oxo-benzomorphans by treatment with a weak base such as sodium orammonium bicarbonate in aqueous ethanol or, alternatively, by treatmentwith activated aluminum oxide in aqueous dimethylsulfoxide. The reactionis believed to proceed by fast formation of the bromoenamines of formulaIV (step 2) which slowly hydrate to carbinol amines of formula VI (step3) with subsequent rearrangement to products of formula I. In carryingout the hydrolysis of the compounds of formula III, the type andquantity of base, the mode of addition of the base, the solvent effectand the temperature and the duration of the reaction all affect yieldsof the formula I products.

Preferred reaction conditions for hydrolyzing bromoenaminium bromides(III) to 9-oxo-6,7-benzomorphans I comprise adding an aqueous solutionof one molecular equivalent of ammonium bicarbonate dropwise in a periodof 1 to 2 hours to a solution of III in 95% ethanol while maintaining atemperature of -5° to -15°, followed by stirring of the reaction mixtureat -5° to -15° for a period of 1.0 to 3.0 hours, and then at roomtemperature for a period of 20-28 hr. The 9-oxo-benzomorphans of formulaI are obtained in this manner in yields ranging from 35 to 65%.Substantially lower yields are, however, obtained if the bicarbonatesolution is added all-at-once to the formula III compound. When strongerbases such as sodium hydroxide, potassium hydroxide or ammoniumhydroxide are employed the yields of I are almost nil*. For instance,when an aqueous ethanol solution of IIIa (R₁ =R₃ =methyl, R₂ =allyl) istreated with one or two equivalents of sodium hydroxide, or ammoniumhydroxide the product isolated contained only a trace of the desired9-oxo-benzomorphan of formula I.

In the initial stage of step 2, the bromoenaminium compound of formulaIV precipitates as a solid or oil and then slowly dissolves as thereaction progresses. The formula IV intermediates may be isolated, ifdesired, and then treated with aqueous ethanol to provide formula Iproducts.

As shown in Chart I, base treatment of formula III compounds (step 2)proceeds in two directions providing bromoenamines of formula IV whichare precursor of the products of formula I along with substances offormula V which are not precursors of formula I compounds. The ratio ofIV and V is dependent upon the base employed. With strong bases such assodium hydroxide, potassium hydroxide, and ammonium hydroxide the majorproduct is the unwanted contaminant V.

The benz[e]indoline intermediates of formula II are synthesizedaccording to processes outlined in Charts II, III and IV. ##STR18##

Step 1 of the process outlined in Chart II is carried out by alkylationof 7-(benzyloxy or alkoxy)substituted-2-tetralones VII according to theprocedure described by Murphy, et al., J. Org. Chem. 25, 1386 (1960) toprovide 1-mono-substituted compounds of formula VIII in 60-95% yields.In step 2, the sodium enolates of VIII are alkylated with ethylbromoacetate in dimethylformamide to provide 1,1-disubstitutedderivatives of formula IX. Reaction of formula IX compounds with excessamine of formula R₃ --NH₂ wherein R₃ is as defined above in an alkanolsolvent such as ethanol at room temperature provides hydroxy lactams Xin 80-90% yields (step 3). The formula X hydroxy lactams are relativelystable in crystalline form and in soluton at temperatures below 40°. Athigh temperatures, water is eliminated and hydroxy lactams X arequantitatively converted to unsaturated lactams of formula XI (step 4).The conversion to XI is preferably carried out by refluxing a solutionof X in reaction inert solvents such as benzene or toluene with acatalytic amount of an acid such as p-toluenesulfonic acid. Reduction ofthe unsaturated lactams XI with lithium aluminum hydride in a reactioninert solvent such as ether provides corresponding enamines of formulaII in yields of 90-98%. Overall yields of this 5-step reaction based onthe tetralone starting materials of formula VII range from about 25 to65%. Representative examples of benz[e]indolines of formula II andoverall yields of the 5-step process based on the tetralones startingmaterials of formula VII are given in Table II below.

                  TABLE II                                                        ______________________________________                                        Yields of Formula II Compounds From Tetralones VII                            Compound                                                                              R.sub.1 R.sub.2          R.sub.3                                                                             Yield                                  ______________________________________                                        (IIa)   methyl  allyl            methyl                                                                              62%                                    (IIb)   methyl  methyl           methyl                                                                              58%                                    (IIc)   benzyl  allyl            methyl                                                                              51%                                    (IId)   methyl                                                                                 ##STR19##       methyl                                                                              27%                                    ______________________________________                                    

The benz[e]indolines of formula II are light-brown colored oilysubstances very sensitive to air and are preferably used in thepreparation of the compounds of formula I immediately after preparationwith all operational manipulation required for synthesis, such asfiltration, evaporation and release of vacuum, performed under anitrogen atmosphere. When storage of the benz[e]indolines of formula IIis required, they are converted to a picrate salt which can be stored atroom temperature for several months and then quantitatively converted tothe benz[e]indoline bases by alkaline treatment. ##STR20##

Chart III illustrates the synthesis of benz[e]indolines of formula IIfrom 2-tetralone starting materials of formula VII. In step 1,conversion of formula VII to enamines of formula XII is carried outaccording to conventional procedures described by D. A. Evans, et al.,J. Org. Chem. 35, 4122 (1970). Treating enamines of formula XII withisopropyl magnesium chloride provides "bidentate" nucleophiles which arethen alkylated by reaction with bromochlorethane (refer to Evans, et al.supra) to produce benz[e]indolines of formula XIII in 95 to 99% yield(step 2). In step 3, the benz[e]indolines of formula XIII are alkylatedat the "9b" position with R₃ X halides wherein R₃ is as defined aboveand X is halogen (preferably chlorine or bromine). To some extentN-alkylation is a competing reaction and the ratio of the desiredC-alkylated products of unwanted N-alkylated compounds varies with thealkylating agent and the solvent. Thus, alkylation of XIII with allylbromide in acetonitrile proceeds mainly by C-alkylation to produce thecorresponding 9b-allyl hydrobromides XIV in 65-75% yields as purecrystalline salts. The effect of the solvent is more pronounced whenbenzyl chloride was employed as the alkylating agent. For instance,reaction of XIIIe (R₁ =R₃ =methyl) with benzyl chloride in a reactioninert solvent such as benzene or dioxane or preferably acetonitrileproduced XIVe (R₁ =R₃ =methyl) isolated as the picrate salt in yields of10, 39, and 46%, respectively. Alkylation of XIIIe with methyl iodide inbenzene or acetonitrile provides the "methiodide" of XIIIe as the majorproduct. Formula XIV intermediates are purified either bycrystallization as hydro-halide salts or by conversion to crystallinepicrate salts. Such salts are stable and can be conveniently stored atroom temperature for several months and when treated with base arequantitatively converted to the benz[e]indolines of formula II.##STR21##

The reaction scheme of Chart IV illustrates an alternate preparation of9b-allyl-3-cyclopropylmethyl-8-methoxy-1,2,4,5-tetrahydro-3H-benz[e]indole(IIe) and9b-allyl-3-cyclobutylmethyl-8-methoxy-5,9b-dihydrobenz[e]indoline (IIf).

As indicated hereinabove, one aspect of the instant invention isconcerned with a process for preparing2'-alkoxy-2,5-di-substituted-9-oxo-6,7-benzomorphan compounds of formulaI ##STR22## wherein R₁ is lower alkyl or benzyl;

R₂ is lower alkyl, allyl, benzyl, or ##STR23## R₃ is lower alkyl,##STR24## in which R₄ is hydrogen or methyl; which comprises sequentialsteps of,

(a) brominating a dihydrobenz[e]indoline of formula II ##STR25## inwhich R₁, R₂, and R₃ are as recited above to produce a bromoenaminiumbromide compound having formula III ##STR26## in which R₁, R₂, and R₃are as recited above; (b) treating the formula III compound with abicarbonate base or activated aluminum oxide to produce the9-oxo-6,7-benzomorphan compound of formula I.

Preferred embodiments of the foregoing process for the preparation ofthe 6,7-benzomorphan compounds characterized by formula I are thosewherein:

(1) the formula II compound employed is that wherein R₁ and R₃ aremethyl and R₂ is allyl;

(2) the formula II compound employed is that wherein R₁, R₂ and R₃ aremethyl;

(3) the formula II compound employed is that wherein R₁ is benzyl, R₂ isallyl, and R₃ is methyl;

(4) the formula II compound employed is that wherein R₁ and R₃ aremethyl and R₂ is (3-ethylenedioxy)butyl;

(5) the formula II compound employed is that wherein R₁ is methyl, R₂ isallyl and R₃ is cyclopropylmethyl;

(6) the formula II compound employed is that wherein R₁ is methyl, R₂ isallyl and R₃ is cyclobutylmethyl;

(7) the formula II compound employed is that wherein R₁ is benzyl, R₂ isallyl and R₃ is cyclobutylmethyl;

(8) the formula II compound employed is that wherein R₁ and R₃ aremethyl and R₂ is benzyl;

(9) In step (a), the bromination is carried out by combining batchwise amethylene chloride solution of the formula II benz[e]indoline and asolution of bromine in methylene chloride at a temperature in the rangeof -40° to -70°;

(10) In step (a), the bromination reaction is carried out at atemperature of -40° to -70° for a period of 5-15 minutes and then atroom temperature for 15-30 minutes;

(11) In step (a), the bromination reaction is carried out at atemperature of -60° for a period of 5-15 minutes and completed at roomtemperature in 15-30 minutes;

(12) In step (b), the bicarbonate base is selected from the groupconsisting of potassium bicarbonate, sodium bicarbonate and ammoniumbicarbonate;

(13) In step (b), an ethanolic solution of the formula III compound andan aqueous solution of one molecular equivalent of a bicarbonate baseselected from the group consisting of sodium bicarbonate, potassiumbicarbonate, and ammonium bicarbonate are combined dropwise in a periodof 1-2 hours at a temperature of -5° to -15°, followed by stirring thereaction mixture at -5° to -15° for a period of 1-3 hours and then atroom temperature for a period of 20-28 hours.

(14) In step (b), the formula III compound is treated with activatedaluminum oxide in aqueous dimethylsulfoxide.

A preferred embodiment in the process for preparing2'-alkoxy-2,5-di-substituted-9-oxo-6,7-benzomorphan compounds of formulaI ##STR27## wherein R₁ is lower alkyl or benzyl;

R₂ is lower alkyl, allyl, benzyl, or ##STR28## R₃ is lower alkyl,##STR29## in which R₄ is hydrogen or methyl; which comprises sequentialsteps of,

(a) combining rapidly batchwise a methylene chloride solution of adihydro[e]indoline of formula II ##STR30## wherein the symbols "R₁, R₂and R₃ " are as recited above with an equimolar amount of bromine inmethylene chloride at a temperature of about -60° under a nitrogenatmosphere, followed by stirring for about 10-15 minutes at -60° andfinally at room temperature for about 20-30 minutes;

(b) treating the formula III compound in ethanol with an aqueoussolution of a bicarbonate base selected from the group consisting ofsodium bicarbonate, potassium bicarbonate and ammonium bicarbonate.

A preferred embodiment in the process for preparing2'-alkoxy-2,5-di-substituted-9-oxo-6,7-benzomorphan compounds of formulaI ##STR31## wherein R₁ is lower alkyl or benzyl;

R₂ is lower alkyl, allyl, benzyl, or ##STR32## R₃ is lower alkyl,##STR33## in which R₄ is hydrogen or methyl; which comprises sequentialsteps of,

(a) combining rapidly a methylene chloride solution of adihydro[e]indoline of formula II ##STR34## wherein the symbols "R₁, R₂and R₃ " are as recited above with an equimolar amount of bromine inmethylene chloride at a temperature of about -60° under a nitrogenatmosphere, followed by stirring for about 10-15 minutes at -60° andfinally at room temperature for about 20-30 minutes;

(b) treating the formula III compound with activated aluminum oxide.

Another aspect of the invention is directed to a process for preparingbenz[e]indolines having formula II ##STR35## wherein R₁ is lower alkylor benzyl;

R₂ is lower alkyl, allyl, benzyl, or ##STR36## R₃ is lower alkyl,##STR37## in which R₄ is hydrogen or methyl; which comprises sequentialsteps of:

(a) reacting a compound of formula IX ##STR38## wherein R₁ and R₂ are asrecited above with an amine of the formula R₃ 13 NH₂ wherein R₃ is asrecited above to produce a hydroxy lactam compound having formula X##STR39## in which R₁, R₂, and R₃ are as recited above; (b) heating theformula X compound above 40° to produce an unsaturated lactam havingformula XI ##STR40## in which R₁, R₂ and R₃ are as recited above; (c)reducing the carbonyl function of compound XI by treatment with lithiumaluminum hydride in a reaction inert solvent to provide the compound offormula II.

Preferred embodiments of the foregoing process for the preparation ofthe benz[e]indoline compounds characterized by formula II are thosewherein:

(1) In step (a), a solution of X in benzene is refluxed;

(2) In step (b), a solution of X in benzene is refluxed with a trace ofp-toluenesulfonic acid.

A further aspect of the invention is directed to a process for preparingbenz[e]indolines having formula II ##STR41## wherein R₁ is lower alkylor benzyl;

R₂ is lower alkyl, allyl, benzyl, or ##STR42## R₃ is lower alkyl,##STR43## in which R₄ is hydrogen of methyl; which comprises sequentialsteps of:

(a) alkylating a compound of formula XIII ##STR44## in which R₁ and R₃are as recited above with R₂ X wherein R₂ is as defined above and X ishalogen in a reaction inert solvent to produce a compound having formulaXIV ##STR45## in which R₁, R₂ and R₃ are as recited above; (b)neutralizing the formula XIV compound to provide the compound of formulaII.

Another embodiment of the instant invention concerns a process forpreparing benz[e]indolines having formula IIe and IIf ##STR46## whereinR is cyclopropylmethyl or cyclobutylmethyl which comprises hydrolyzing acompound of formula XIX ##STR47## wherein R is cyclopropylmethyl orcyclobutylmethyl with dilute solution of a strong acid such ashydrochloric acid, sulfuric acid or phosphoric acid.

As used herein, the term "reaction inert solvent" refers to a solventthat does not enter into a reaction to the extent that it emergesunchanged from the reaction.

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. It isto be understood that the invention is not limited solely to theparticular examples given below. All temperatures expressed herein arein degrees centigrade. IR means infrared spectrum. The nuclear magneticresonance (NMR) spectra were recorded on a Varian A-60A spectrometerusing deuteriochloroform as a solvent. The chemical shifts are expressedin δ values using tetramethylsilane as internal reference.

EXAMPLE 1 ##STR48## 1-Allyl-3,4-dihydro-7-methoxy-2(1H)naphthalenone.

To a solution of 104.1 g (0.59 mole)3,4-dihydro-7-methoxy-2(1H)naphthalenone in 100 ml dry benzene was addeddropwise under nitrogen with stirring at room temperature 62.5 g (0.88mole) pyrrolidine. After the addition (10-15 min), the reaction mixturewas refluxed for 2.5 hr with azeotropic removal of water and then cooledto room temperature. The enamine solution was added dropwise to 143.8 g(1.19 mole) allyl bromide with stirring at a rate sufficient to maintainnormal refluxing to provide a heavy precipitate. Benzene (50 ml) wasadded to facilitate stirring and reflux continued for 4 hr; then, 700 mlof water was added and refluxing resumed. After 2 hr, the reactionmixture was cooled to room temperature and diluted with 100 ml benzene.The benzene layer was separated and the aqueous phase extracted withbenzene (2×100 ml). The combined extracts were washed with water (2×100ml) and dried (Na₂ SO₄). After evaporation of the solvent, the residuewas distilled to give 113.5 g (89%) of VIIIa, b.p. 114°-118°/0.1-0.05 mmHg. NMR: δ 2.40-3.10 (m, 6, allylic and alicyclic), 3.45 (t, 1, C₁ --H,J=6.5), 3.75 (s, 3, OCH₃), 4.8-6.1 (m, 3, olefinic), 6.7-7.2 (m, 3,ArH). IR: (neat) 1715 cm⁻¹

EXAMPLE 2 ##STR49## 3,4-Dihydro-7-methoxy-1-methyl-2(1H)naphthalenone.

This compound was prepared in 84% yield according to the methoddescribed by Murphy, et al., J. Org. Chem. 25, 1386 (1960); b.p.110°-112°/0.3-0.4 mm Hg; NMR: δ 1.43 (d, 3, CH₃, J=7.0 Hz), 3.68 (s, 3,OCH₃), 6.65-7.20 (m, 3, ArH).

EXAMPLE 3 ##STR50## 1-Allyl-7-benzyloxy-3,4-dihydro-2(1H)-naphthalenone.

To a mixture of 22.7 g (0.09 mole)3,4-dihydro-7-benzyloxy-2-(1H)naphthalenone and 50 ml dry benzene wasadded dropwise at room temperature a solution of 9.6 g (0.135 mole)pyrrolidine in 50 ml benzene with stirring under a nitrogen atmosphere.After the addition (10 min), the reaction mixture was refluxed withazeotropic removal of water for 3 hr and then cooled to roomtemperature. A solution of 22.0 g (0.181 mole) allyl bromide in 25 mlbenzene was added dropwise (10 min) to the reaction mixture which wasthen heated to reflux to provide a heavy precipitate. Benzene (100 ml)was added to facilitate stirring and refluxing continued for 4 hr. Water(200 ml) was added and reflux continued for another 2 hr. After thereaction mixture cooled to room temperature, the benzene phase wasseparated and the aqueous phase was extracted first with benzene (50 ml)and then with ether (100 ml). The combined extracts were washed withwater (100 ml), dried (Na₂ SO₄) and evaporated to dryness to give 24.8 g(94%) of liquid VIIIc. NMR: δ 5.15 (s, 2, PhCH₂ O), 4.8-6.1 (m, 5,olefinic plus PhCH₂ O), 6.80-7.50 (m, 8, ArH). IR: (CHCl₃), 1715 cm⁻¹.

Anal. Calcd. for C₂₀ H₂₀ O₂ : C, 82.14; H, 6.89. Found: C, 80.72; H,6.75.

This material was used without further purification in Example 7.

EXAMPLE 4 ##STR51##Ethyl-7-methoxy-2-ozo-1,2,3,4-tetrahydro-1-naphthaleneacetate.

This compound was prepared in 78% yield according to Wiesner, et al.,Can. J. Chem., 49, 1092 (1971).

EXAMPLE 5 ##STR52##Ethyl-1-allyl-7-methoxy-2-oxo-1,2,3,4-tetrahydro-1-naphthaleneacetate.

Into a flame-dry 500 ml 3-neck flask provided with mechanical stirrer,dropping funnel and a nitrogen inlet tube was placed 4.21 g sodiumhydride (55% dispersion in oil, 100 mmol) with the apparatus placedunder nitrogen. The oil was washed out with benzene (3×30 ml), 40 ml drydimethylformamide was added and the suspension was stirred and cooled inan ice-bath. A solution of 21.6 g (100 mmol)1-allyl-3,4-dihydro-7-methoxy-2(1H)naphthalenone (VIIIa) in 10 mldimethylformamide was added dropwise (10 min), then the cooling bath wasremoved and stirring at room temperature continued until the evolutionof gas ceased (2 hr). The brown-colored reaction mixture was cooled(ice-bath) and a solution of 16.7 g (100 mmol) ethyl bromoacetate in 40ml dimethylformamide was added dropwise keeping the reaction temperaturebelow 25° C. After the addition (15-20 min) stirring in cold wascontinued for 1 hr and then overnight at room temperature. Water (300ml) was added and extracted with ether (3×100 ml). The combined etherextracts were washed with water (2×100 ml) dried (MgSO₄), the solventremoved by evaporation and the residue was distilled to give 26.0 g(86%) IXa, b.p. 145°-150°/0.05-0.01 mm Hg; IR (neat) 1740, 1715 cm⁻¹ ;NMR δ, 1.05 and 3.92 (triplet and quartet for OCH₂ CH₃), 3.75 (s, 3,OCH₃), 4.65-6.0 (m, 3, CH═CH₂), 6.55-7.15 (m, 3, ArH).

Anal. Calcd for C₁₈ H₂₂ O₄ : C, 71.50; H, 7.33. Found: C, 71.27; H,7.28.

EXAMPLE 6 ##STR53##Ethyl-7-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-1-naphthaleneacetate.

The compound 3,4-dihydro-7-methoxy-1-methyl-2(1H)-naphthalenone (VIIIb)(28.23 g, 148 mmol) was reacted with ethyl bromoacetate by the method ofExample 5 to yield 36.0 g (88%) (IXb) b.p. 138°-140°/0.1 mm Hg; IR(neat) 1740 cm⁻¹ (unresolved ketone and ester bands); NMR δ, 1.05 and3.93 (triplet and quartet for CO₂ CH₂ CH₃), 1.37 (s, 3, CH₃), 3.80 (s,3, OCH₃), 6.6-7.3 (m, 3, ArH). The distillate crystallized on standing.A sample recrystallized from ethanol melted at 55°-55.5°.

Anal. Calcd. for C₁₆ H₂₀ O₄ : C, 69.54; H, 7.29. Found: C, 69.75; H,7.33. The distilled product was used in Example 10.

EXAMPLE 7 ##STR54##Ethyl-1-allyl-7-benzyloxy-2-oxo-1,2,3,4-tetrahydro-1-naphthaleneacetate.

Crude 1-allyl-7-benzyloxy-3,4-dihydro-2(1H)-naphthalenone (VIIIc), 22.9g (78.5 mmol) was reacted with ethyl bromoacetate by the method ofExample 5 to yield 25.5 g (87%) crude crystalline IXc. Recrystallizationfrom ethanol gave 19.5 g (66%) m.p. 83°-85°. IR (CHCl₃) 1725, 1710 cm⁻¹(ketone and ester); NMR δ, 1.05 and 3.96 (triplet and quartet for OCH₂CH₃) 4.8-5.8 (m, 5, olefinic and PhCH₂ O), 5.15 (s, 2, PhCH₂ O),6.80-7.55 (m, 8, ArH).

Anal. Calcd. for C₂₄ H₂₆ O₄ : C, 76.16; H, 6.92. Found: C, 76.09; H,6.96.

EXAMPLE 8 ##STR55##Ethyl-1-(3-ethylenedioxy)butyl-7-methoxy-2-oxo-1,2,3,4-tetrahydro-1-naphthaleneacetate.

This compound was prepared in 87% yield fromethyl-7-methoxy-2-oxo-1,2,3,4-tetrahydro-1-naphthaleneacetate (VIIId)according to Wiesner, et al., Can. J. Chem. 49, 1092 (1971) and usedwithout purification in Example 12.

EXAMPLE 9 ##STR56##9b-Allyl-3a-hydroxy-8-methoxy-3-methyl-2-oxo-2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole.

Methylamine (gas) 6.80 g (220 mmol) was added to ethanol in an openflask. This solution was added to 21.2 g (70 mmol)ethyl-1-allyl-7-methoxy-1,2,3,4-tetrahydro-1-naphthaleneacetate (IXa)and the clear solution left at room temperature for 24 hr to provide acrystalline product which was filtered to give 12.5 g (62%) Xa, m.p.146°-149°. From the mother liquor, after evaporation (35°) and treatmentof the residue with ether (50 ml), 3.8 g, m.p. 147°-150° additional Xawas obtained, increasing the yield to 81.5%; IR (CHCl₃) 3500 (broadband), 1690, 1615, 1505, cm⁻¹ ; NMR 2.88 (s, 3, N-CH₃), 3.92 (s, 3,OCH₃), 4.62 (broad singlet, OH), 4.9-6.1 (m, 3, olefinic), 6.8-7.3 (m,3, ArH).

Anal. Calcd. for C₁₇ H₂₁ HO₃ : C, 71.05; H, 7.37; N, 4.87. Found: C,70.90; H, 7.38; N, 4.67.

EXAMPLE 10 ##STR57##3,9b-Dimethyl-3a-hydroxy-8-methoxy-2-oxo-2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole.

A solution of 22.0 g (79.7 mmol)ethyl-7-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-1-naphthaleneacetate(IXb) and 7.5 g (240 mmol) methylamine in 25 ml ethanol was left at roomtemperature for 24 hr. The crystalline precipitate formed was separatedto give 15.5 g (74.5%) Xb, m.p. 182°-186°. From the mother liquor, afterevaporation (35°) and treatment with ether, 1.0 g, additional Xb wascollected increasing the yield to 79.5%; IR (Nujol), 3300 (OH), 1670cm⁻¹ (lactam); NMR (CDCl₃ -DMSO) δ, 1.48 (s, 3, CH₃), 2.82 (s, 3,N-CH₃), 3.78 (s, 3, OCH₃), 6.6-7.1 (m, 3, ArH).

Anal. Calcd. for C₁₅ H₁₉ NO₃ : C, 68.94; H, 7.32; N, 5.36. Found: C,68.74; H, 7.30; N, 5.53.

EXAMPLE 11 ##STR58##9b-Allyl-8-benzyloxy-3a-hydroxy-3-methyl-2-oxo-2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole.

A mixture of 6.30 g (167 mmol)ethyl-1-allyl-7-benzyloxy-2-oxo-1,2,3,4-tetrahydro-1-naphthaleneacetate(IXc), 31.0 g methylamine and 200 ml 1:1 ethanol-dioxane was stirred atroom temperature for 3 days. The reaction mixture was concentrated byevaporation of the solvent (35°-40° C.) to half the volume and dilutedwith 200 ml ether to provide a crystalline product which was collectedto give 51.0 g (86%) Xc, m.p. 188°-190°; IR (Nujol), 3250, (broad),1665, 1615, 1505 cm⁻¹.

Anal. Calcd. for C₂₃ H₂₅ NO₃ : C, 76.00; H, 6.93; N, 3.85. Found: c,75.89; H, 6.87; N, 3.90.

EXAMPLE 12 ##STR59##9b-(3-Ethylenedioxy)butyl-8-methoxy-3a-hydroxy-3-methyl-2-oxo-2,2,3a,4,5,9b-hexahydro-1H-benz[e]indole.

To a solution of 15.0 g (0.5 mole) methylamine in 50 ml ethanol wasadded 30.0 g (80 mmol) ofethyl-1-(3-ethylenedioxy)butyl-7-methoxy-2-oxo-1,2,3,4-tetrahydro-1-naphthaleneacetate(IXd). After standing at room temperature for 49 hr, the solvent wasremoved by evaporation to provide Xd as a dark-brown syrup which wasused without further purification in Example 16.

EXAMPLE 13 ##STR60##9b-Allyl-8-methoxy-3-methyl-2-oxo-2,3,5,9b-tetrahydro-1H-benz[e]indole.

A solution of 14.0 g (48.7 mmol) Xa and 24 mg p-toluenesulfonic acid in100 ml benzene was refluxed for 2 hr with azeotropic distillation ofwater using a Dean-Stark trap. After cooling to room temperature, thesolution was washed with water and dried. Removal of the solvent on arotary evaporator gave 13.0 g (100%) XIa as a pale-yellow syrup; IR(neat) 1725, 1685, 1615, 1505 cm⁻¹ ; NMR δ 2.24 (d, 2, allylic, J=7.0Hz), 2.75 (s, 2, CH₂ CO), 2.94 (s, 3, NCH₃), 3.34 (m, s, benzylic), 3.75(s, 3, OCH₃), 4.75-5.85 (m, 4, olefinic), 6.5-7.2 (m, 3, ArH).

Anal. Calcd. for C₁₇ H₁₉ NO₂ : C, 75.80; H, 7.11; N, 5.20. Found: C,75.93; H, 7.10; N, 5.19.

EXAMPLE 14 ##STR61##3,9b-Dimethyl-8-methoxy-2-oxo-2,3,5,9b-tetrahydro-1H-benz[e]indole.

A solution of 11.25 g (43.2 mmol) and 25 mg p-toluenesulfonic acid in100 ml toluene was refluxed for 2 hr with azeotropic removal of water.After cooling to room temperature, the solution was washed with waterand dried (Na₂ SO₄). Removal of the solvent in vacuo and trituration ofthe residue with ether (20 ml) gave 9.5 g (90%) crystalline XIb, m.p.106°-108°; IR (CHCl₃) 1725, 1685 cm⁻¹ ; NMR δ, 1.27 (s, 3, CH₃), 2.72and 2.76 (s, 2, CH₂ CO), 2.95 (s, 3, NCH₃), 3.34 (m, 2, benzylic), 3.78(s, 3, OCH₃), 5.14 (dd, 1, NC═CH, J₁ =5.0, J₂ =3.5 Hz), 6.7-7.3 (m, 3,ArH).

Anal. Calcd. for C₁₅ H₁₇ NO₂ : C, 74.04; H, 7.04; N, 5.75. Found: C,74.28; H, 7.06; N, 5.89.

Crude XIb, obtained in quantitative yield as a solid, was used withoutpurification in Example 18.

EXAMPLE 15 ##STR62##

9b-Allyl-8-benzyloxy-3-methyl-2-oxo-2,3,5,9b-tetrahydro-1H-benz[e]indole.

This compound was obtained quantitatively from Xc by the procedure ofExample 14 and was used in Example 19 without further purification; IR(neat) 1725, 1685, 1610, 1505 cm⁻¹ ; NMR 67, 2.26 (d, 2, allylic, J=7.0Hz), 2.78 (s, 2, CH₂ CO), 3.0 (s, 3, NCH₃), 3.41 (m, 2, benzylic),4.8-5.8 (m, 6, olefinic, PhCH₂ O), 6.7-7.6 (m, 8, ArH).

EXAMPLE 16 ##STR63##9b-(3-Ethylenedioxy)butyl-8-methoxy-3-methyl-2-oxo-2,3,5,9b-tetrahydro-1H-benz[e]indole.

Crude Xd from Example 12 was dissolved in toluene, 50 mgp-toluenesulfonic acid added and the solution refluxed for 1 hr withazeotropic removal of water. The solvent was removed by evaporation andthe residue was dissolved in ethanol (25 ml), diluted with ether (120ml) and allowed to crystallize at room temperature. The crystalline XIdwas separated by filtration to give 7.0 g. The mother liquor, afterevaporation to dryness, was dissolved with a small amount of CH₂ Cl₂ andpassed through a sintered glass funnel packed with silica (6 cm long×9.5cm I.D.) and washed with 4% EtOH-CH₂ Cl₂. After evaporation of thesolvent, the dark-brown residue, 14.0 g, was dissolved in ether (50 ml)and allowed to crystallize at room temperature. The crystallineprecipitate was filtered to give 5.0 g, additional XId. The motherliquor on cooling to 0° overnight deposited 1.0 g of XId. The abovecrystalline crops were combined to provide a total of 13.0 g (48%) XId.TLC on silica (4% EtOH-CH₂ Cl₂) showed one major spot and a trace ofanother with lower Rf value. Recrystallization from ethanol (35ml)-ether (20 ml) gave 10.0 g analytically pure XId, m.p. 143°-145°; IR(CHCl₃) 1725, 1680, 1610, 1505 cm⁻¹ ; NMR δ, 1.18 (s, 3, CH₃), 2.80 (s,2, CH₂ CO), 3.0 (s, 3, NCH₃), 3.80 (s, 7, OCH₂ CH₂ O and OCH₃), 5.25(dd, 1, NC=CH, J₁ =3.5 and J₂ =5.0 Hz), 6.70-7.35 (m, ArH).

Anal. Calcd. for C₂₀ H₂₅ NO₄ : C, 69.94; H, 7.33; N, 4.07. Found C,69.45; H, 7.67; N, 4.29.

EXAMPLE 17 ##STR64##9b-Allyl-3-methoxy-3-methyl-5,9b-dihydrobenz[e]indoline.

To a suspension of 5.9 g (155 mmol) lithium aluminum hydride in 190 mldry ether was added dropwise under a slow stream of nitrogen andstirring a solution of 28.19 g (104.8 mmol) XIa in 190 ml dry ether atsuch a rate as to maintain gentle refluxing. Following the addition (20min), stirring at room temperature was continued for 2 hrs. The reactionmixture was cooled in an ice bath and treated successively with 5.9 mlwater, 4.4 ml 20% aqueous sodium hydroxide and 20.6 ml water to providea granular precipitate which was filtered under nitrogen and rinsed withether. The combined filtrate and washings were evaporated to dryness ona rotary evaporator under reduced pressure. After removal of the solventwas complete, the flask containing the product was filled with nitrogen.The compound IIa thus obtained consisted of a pale yellow syrup, 26.2 g(98%) and was used in Example 22 immediately after preparation: IR(neat) 1670 cm⁻¹ (N--C═C); NMR δ, 2.60 (s, 3, N--CH₃), 3.68 (s, 3,OCH₃), 4.30 (dd, 1, NC═CH, J₁ =5.5, J₂ =2.5 Hz), 4.63-5.98 (m, 3,olefinic), 6.43-7.0 (m, 3, ArH).

IIa picrate.

When very pure IIa was required and also for storing purposes, IIa wasconverted to the picrate salt as follows. IIa (26.2 g) was dissolved in30 ml ethanol under nitrogen and the solution was added to a boilingsolution of 30 g picric acid in 200 ml ethanol. The crystallineprecipitate was separated by filtration and dried to give 45.0 g (90%),m.p. 147°-148°.

Anal. Calcd. for C₂₃ H₂₄ N₄ O₈ : C, 57.2; H, 5.00; N, 11.56. Found: C,57.15; H, 5.35; N, 11.61.

The picrate salt of IIa is a stable compound and could be stored at roomtemperature for several months. The enamine IIa was regenerated from itspicrate as follows: A mixture of finely powdered picric acid salt of IIa(10 mmol), 50 ml 1 N aqueous lithium hydroxide, 20 ml ethanol and 100 mlether was shaken in a separatory funnel under nitrogen until all thesolids had dissolved. The ether phase was separated and washed withwater, dried (MgSO₄) and evaporated to dryness to quantitatively givethe free base.

EXAMPLE 18 ##STR65##3,9b-Dimethyl-8-methoxy-5,9b-dihydrobenz[e]indoline.

To a stirred suspension of 3.40 g (89.4 mmol) lithium aluminum hydridein 110 ml dry ether under a slow stream of nitrogen was added dropwise asolution of 14.65 g (60.2 mmol) of crude XIb in 500 ml dry ether and atsuch a rate as to maintain normal reflexing. After the addition (25min), stirring was continued at room temperature for 1.5 hr. The productwas isolated according to Example 17 to give 13.42 g (98%) of airsensitive XIb as a pale-brown liquid; IR (neat) 1675 cm⁻¹ (N--C═CH); NMRδ, 1.20 (s, 3, CH₃), 2.67 (s, 3, N.CH₃), 3.74 (s, 3, OCH₃), 4.30 (dd, 1,NC═CH, J₁ =5.5, J₂ =2.5 Hz).

Anal. Calcd. for C₁₅ H₁₉ NO: C, 78.56; H, 8.35; N, 6.10. Found: C,78.06; H, 8.24; N, 5.93.

When the reduction of XIb was carried out in ethertetrahydrofuran, asticky product was obtained which contained very little Ib as evidencedby NMR.

EXAMPLE 19 ##STR66##9b-Allyl-8-benzyloxy-3-methyl-5,9b-dihydrobenz[e]indoline.

Reduction of crude XIc with lithium aluminum hydride in ether by theprocedure of Example 17 afforded IIc; yield, 95%, IR (neat) 1670 cm⁻¹.,(NC═C); NMR δ, 2.70 (s, 3, NCH₃), 4.36 (dd, 1, NC═CH, J₁ =5.5, J₂ =2.5Hz), 4.73-5.90 (m, 3, olefinic), 5.08 (s, 2, PhCH₂ O), 6.25-7.53 (m, 8,ArH).

EXAMPLE 20 ##STR67##9b-(3-Ethylenedioxy)butyl-8-methoxy-3-methyl-5,9b-dihydrobenz[e]indoline.

To a suspension of 0.5 g (13 mmol) lithium aluminum hydride in 50 ml dryether was added portionwise, under nitrogen and stirring 3.43 g (10mmol) of crystalline XId. After the addition (15 min), the mixture wasrefluxed (maintaining the nitrogen atmosphere and stirring) for 45 min.Then, 30 ml ether was added and refluxing continued for a total of 2.5hrs under nitrogen and stirring. The reaction mixture was cooled in anice-bath and excess lithium aluminum hydride was decomposed by dropwiseaddition of water (0.6 ml). After stirring for 45 min, the hydrolyzedmixture was filtered under nitrogen and the filter-cake washed withether. The ether solution after drying was evaporated to dryness to give3.1 g (94%) of IId as a pale yellow syrup; IR (neat) 1670 cm⁻¹ ; NMR δ,1.20 (s, 3, CH₃), 2.65 (s, 3, NCH₃), 3.80 (s, 7, OCH₂ CH₂ O and OCH₃),4.41 (dd, 1, NC═CH, J₁ =5.5, J₂ =2.5 Hz).

EXAMPLE 21 Bromination of benz[e]indolines of formula II. Method A.

To a 0.1 M solution of bromine in methylene chloride previously cooledto -60° (acetone-dry ice) under nitrogen and stirring was added all atonce an equimolar amount of a benz[e]indolines of formula II in the samesolvent (1 mmol in 0.5-1.0 ml). After stirring in cold for 10-15 min andat room temperature for 20-30 min the solvent was removed in vacuo.

Method B.

To a 0.1 M solution of a benz[e]indoline of formula II in methylenechloride previously cooled to -60°, under nitrogen and stirring wasadded dropwise (20 min) an equimolar amount of bromine in the samesolvent (1 mmol in 1.0-2.0 ml). After stirring in cold for 10-15 min andat room temperature for 20-30 min the solvent was removed in vacuo.

EXAMPLE 22 ##STR68##9b-Allyl-4-bromo-8-methoxy-2,4,5,9b-tetrahydro-1H-benz[e]-indolemethobromide.

Bromination of IIa according to Example 21 (method A) gave aquantitative yield of IIIa as a light-brown sticky product. This productwithout purification was used soon after preparation in Example 26.

When IIa was brominated according to Example 21 (method B), thebromination product contained an appreciable amount of the hydrobromideof IIa.

EXAMPLE 23 ##STR69##4-Bromo-9b-methyl-8-methoxy-2,4,5,9b-tetrahydro-1H-benz[e]indolemethobromide.

Compound IIb, 13.4 g (58.6 mmol) was brominated according to Example 21(method A). After removal of the solvent by evaporation, the stickyresidue on trituration with ether solidified. Removal of the ether byevaporation gave 22.8 g (100%) crystalline. IIIb of pale yellow color.An analytical sample was prepared by recrystallization from ethanol,m.p. 125°-127°.

Anal. Calcd. for C₁₅ H₁₉ Br₂ NO.1/2H₂ O: C, 45.24; H, 5.06; Br, 40.13;N, 3.54. Found: C, 45.37; H, 5.10; Br, 39.15; N, 3.51.

EXAMPLE 24 ##STR70##9b-Allyl-8-benzyloxy-4-bromo-2,4,5,9b-tetrahydro-1H-benz[e]indolemethobromide

The benz[e]indoline IIc, 51.2 g (154 mmol) was brominated according toExample 21 (method A) to yield 75.5 g (100%) crude IIIc as a stickyresidue which was used in Example 29 without further purification.

EXAMPLE 25 ##STR71##9b-(3-Ethylenedioxy)butyl-4-bromo-8-methoxy-2,4,5,9b-tetrahydro-1H-benz[e]indolemethobromide.

This compound was prepared in quantitative yield (crude) from IIdaccording to Example 21 (method A) and utilized in Example 30 withoutfurther purification.

EXAMPLE 26 ##STR72##9b-Allyl-4-bromo-8-methoxy-3-methyl-5,9b-dihydrobenz[e]indoline.

(a) To a cold solution (-10°) of 3.75 g (9.05 mmol) IIIa in 55 ml 95%ethanol-water under nitrogen and stirring was added dropwise (45 min) 20ml of 0.5 M solution of ammonium bicarbonate in water. After stirringfor 30 min more at the above temperature, the crystalline precipitatewas fast filtered under nitrogen and dried in a flask under high vacuum.The flask was then filled with nitrogen. The pale yellow crystalline IVa(1.40 g, 47%) melted at 50°-60° (dec), IR (CHCl₃) 1670 cm⁻¹ (strong,N--C═C); NMR δ, 1.85-2.35 (m, 4, allylic and CH₂), 3.14 (s, 3, NCH₃),3.76 (s, 3, OCH₃), 3.14-3.76 (m, 4, benzylic and NCH₂), 4.70-5.80 (m, 3,olefinic), 6.50-7.15 (m, 3, ArH).

(b) In another experiment, an aqueous solution of IIIa was treated withexcess sodium bicarbonate and extracted with ether. The ether extractafter evaporation gave IVa in 55% yield. The dark brown aqueous phaseupon extraction with chloroform and removal of the solvent gave a darkbrown sticky residue, presumably Va (R₁ =R₃ =methyl, R₂ =allyl). Theethereal extract IVa when stirred overnight in 80% ethanol-waterproduced the 9-oxo-benzomorphan Ia. Similar treatment of the chloroformextract did not produce any Ia.

(c) In another experiment, an aqueous solution of IIIa was treated withexcess sodium hydroxide and extracted with ether. Evaporation of theether solution left a syrup IVa in 10-15% yield. The major product wasthe chloroform soluble compound Va of Example 26(b). The product of theether extract but not the chloroform extract could be converted to Ia bytreatment with aqueous ethanol.

(d) In another experiment, IIIa was treated with excess ammoniumhydroxide and extracted with ether. Evaporation of the ether left IV asa syrup in 15% yield.

EXAMPLE 27 ##STR73## 5-Allyl-2'-methoxy-2-methyl-9-oxo-6,7-benzomorphan.Method A.

Into a 250 ml 3-neck flask fitted with mechanical stirrer, droppingfunnel and nitrogen inlet and outlet tubes was added a solution of 8.05g (19.4 mmol) IIIa in 170 ml, 95% ethanol-water and the solution wascooled in an ice-bath and stirred under a slow stream of nitrogen. Asolution of 1.58 g (20 mmol) ammonium bicarbonate in 42 ml water addeddropwise in 1.5 hrs provided a pale yellow crystallline precipitate ofIVa. After stirring in cold for 2 hr, the cooling bath was removed andthe reaction mixture was stirred at room temperature for 24 hr. The darkbrown solution was concentrated by evaporation to a volume of about 50ml. alkalified with 10% sodium hydroxide (50 ml) and extracted withether (3×50 ml) to a pale yellow solution.

After drying and removal of the solvent by evaporation, a syrup residue,4.2 g, was left which was dissolved with 20 ml dry acetone and treatedwith a solution of 2.0 g anhydrous oxalic acid in 20 ml ether andallowed to crystallize first at room temperature and then at 0°overnight. The crystalline product obtained was separated by filtrationto give 4.12 g (58.5%) of oxalate of Ia, m.p. 156°-159°. A sample wasrecrystallized from 94% ethanol-water to give the oxalate monohydratethat melted at 115°-120° solidified and melted at 160°-161°.

Anal. Calcd. for C₁₉ H₂₃ NO₆.H₂ O: C, 60.15; H, 6.64; N, 3.69. Found: C,60.09; H, 6.68; N, 3.56.

The yield of Ia was 64% when the crude product was purified bychromatography on activated aluminum oxide eluted with methylenechloride. The free base was obtained from the oxalate by base treatmentand extraction with ether; IR (neat) 1730 cm⁻¹ ; NMR δ, 2.42 (s, 3,NCH₃), 3.75 (s, 3, OCH₃), 4.70-6.15 (m, 3, olefinic), 6.60-7.15 (m, 3,ArH).

In other runs, the ammonium bicarbonate or sodium bicarbonate was addedat once at the beginning of the reaction. The yields of Ia in thesecases were 35-40%.

In another run, sodium hydroxide was used instead of ammoniumbicarbonate. A product in 10-15% yield was obtained (of deep red color)which contained only traces of Ia as it was evidenced by the smallabsorption IR band at 1730 cm⁻¹. When ammonium hydroxide was used, theresult was the same.

Method B.

A mixture of 3.78 g (9.08 mmol) IIIa and 20.0 g aluminum oxide G type Efor thin layer chromatography (Merck, Germany) in 40 ml 75%dimethylsulfoxide-water was stirred under nitrogen at room temperaturefor 24 hr. It was filtered and the cake washed with ethanol (2×15 ml)and water (2×20 ml). The combined filtrate and washings were dilutedwith water (50 ml), treated with 10% sodium bicarbonate (50 ml) andextracted with ether (4×50 ml). The ethereal extract was washed withwater (3×50 ml) dried (MgSO₄), decolorized with Alumina Act. II (5.0 g)and filtered. Removal of the solvent by evaporation and treatment of theresidue (1.7 g) with anhydrous oxalic acid as in Method A gave 1.80 g(55%) of the oxalate of Ia m.p. 156°-159°.

EXAMPLE 28 ##STR74## 2'-Methoxy-2,5-dimethyl-9-oxo-6,7-benzomorphan.

(a) Exmploying the procedure of Example 27 (method A) a solution of 1.64g (20.6 mmol) ammonium bicarbonate in 42 ml water was added dropwise in1.5 hr under nitrogen to a solution of 7.78 g (20 mmol) crude IIIb in175 ml, 95% ethanol-water, previously cooled in an ice-salt bath withstirring. After the addition, stirring in cold was continued for 2 hrand at room temperature for 24 hr. The brown solution was evaporated tonear dryness and treated with 50 ml water and 50 ml 10% NaHCO₃ andextracted with ether (5×50 ml). The combined ethereal extracts werewashed with water (2×50 ml) to a pale yellow solution. After drying(MgSO₄) and removal of the solvent by evaporation, the liquid residue(3.46 g, 70.6%) was dissolved with 10 ml dry acetone and treated with asolution of 2.0 g anhydrous oxalic acid in 10 ml acetone. The solutionwas allowed to crystallize first at room temperature and then at 0°overnight. The crystalline product was filtered and washed with acetone(20 ml) and dried to give 3.91 g (58%) of the oxalate of Ib, m.p.136°-142°. The oxalate was quantitatively converted to the free base bytreatment with ammonium hydroxide and extraction with chloroform. Thefree base shows a single spot on TLC (Alumina, 1% methanol in methylenechloride). The free base was dissolved in ether and converted to thehydrochloride (HCl, gas). Recrystallization of the hydrochloride from95% ethanol-water gave the hydrochloride of the ethanol hemiacetal (noCO in IR; CH₃ CH₂ O-- on NMR), m.p. 122°-144°. When the m.p. was takenslowly, the compound melted at 122° solidified and melted at 186°-188°.Recrystallization of the hydrochloride of Ib from water (2 ml/g)-acetone(10 ml/g) gave the hydrochloride monohydrate, m.p. 130°-132°.

The free base, IR (neat), 1730 cm⁻¹ ; NMR δ, 1.36 (s, 3, CH₃), 2.32 (s,3, NCH₃), 3.65 (s, 3, OCH₃), 6.5-7.1 (m, 3, ArH).

(b) Employing the procedure of Example 27 (method B), a mixture of 3.89g (10 mmol) IIIb and 23.0 g activated aluminum oxide in 90 ml, 75%DMSO-water was stirred under nitrogen for 24 hrs. It was filtered andthe cake washed with ethanol (2×15 ml) and water (2×20 ml). The combinedfiltrate and washings was diluted with 250 ml water, treated with 10%NaHCO₃ (50 ml) and extracted with ether (7×50 ml). The ether extractswere washed with water (2×50 ml) dried and evaporated to dryness. Theliquid residue (1.74 g, 71%) was converted to the oxalate as in Example27 (method A) to give 1.97 g (58.5%) of Ib.

(c) Preparation according to the process of Takeda et al J. Org. Chem.37, 2677 (1972).

To a solution of 3.89 g (10 mmol) IIIb in 88 ml methylene chloridepreviously cooled in an ice-bath was added 25 ml water. After stirringfor 30 min, aqueous ammonium hydroxide (30 ml of 3%) was added andstirring continued for 2 hr in cold and 20 hr at room temperature. Theorganic phase was separated and the aqueous phase extracted withchloroform (2×50 ml). The combined extracts (deep red color) were washedwith water (2×50 ml), dried and evaporated to dryness to give 2.4 g darkred oil. TLC (Alumina, 1% MeOH--CH₂ Cl₂) shows at least five spots. IRshows a band at 1730(CO) and a band at 1670 cm⁻¹ (NC═C) in a ratio ofintensities of about 1:3 verifying the TLC observation that small amountof ketone was present in the mixture. The crude product waschromatographed on a column packed with Alumina Act. II to give a bed 19cm long, 3.5 cm I.D. The column was eluted: (a) with 620 ml benzene togive 60 mg syrup; IR shows CO and NC═C. (b) after standing overnight itwas eluted with 500 ml methylene chloride, removal of the solvent gave50 mg syrup with same IR spectrum as the fraction above. (c) with 520ml, 5% ethanol-CH₂ Cl₂ ; removal of the solvent gave 1.1 g dark-redsyrup; IR showed CO and N--C═C bands in a ratio of 2:1 (d) withmethanol; removal of the solvent by evaporation gave 1.1 g dark-redsticky material. This was dissolved in methylene chloride washed with10% NaHCO₃ (to convert any hydrobromide salt to the free base) dried andevaporated to dryness to give 0.9 g syrup, IR shows CO and NC═C bands.

The last two fractions (c and d) were combined and treated with ether(100 ml). Insoluble material was removed by filtration. The filtrate waswashed with water (2×50 ml) to a pale yellow solution. After drying andremoval of the solvent by evaporation, the liquid residue (0.9 g) wasconverted to the oxalate as above to give 0.7 g (21%) of Ib, m.p.130°-138°.

EXAMPLE 29 ##STR75##5-Allyl-2'-benzyloxy-2-methyl-9-oxo-6,7-benzomorphan.

The compound IIIc (17.2 g, 35 mmol) was treated with ammoniumbicarbonate in aqueous ethanol as described in Example 27 (method A) togive 10.7 g crude product as a syrup which was dissolved in dry-ether,polish filtered, and treated with an ethereal solution of anhydrousoxalic acid. The oxalate was recrystallized from 95% ethanol (10ml)-acetone (40 ml) to give 7.4 g (42%) of th Ic oxalate, m.p.104°-107°. IR (neat) of free base 1730 cm⁻¹ ; NMR δ, 2.40 (s, 3, NCH₃),4.90 (s, 2, PhCH₂ O), 4.85-6.15 (m, 3, olefinic), 6.60-7.30 (m, 8, ArH).

Anal. Calcd. for C₂₅ H₂₇ NO₆.H₂ O: C, 65.91; H, 6.41; N, 3.07. Found: C,65.17; H, 6.41; N, 2.89.

EXAMPLE 30 ##STR76##5-(3-Ethylenedioxy)butyl-2'-methoxy-3-methyl-9-oxo-6,7-benzomorphan.

The crude bromoenaminium bromide IIId (9.1 mmol) was treated withammonium bicarbonate in aqueous ethanol as described in Example 27(method A). The crude product was purified by dry-column chromatography(silica, ether), to give 1.1 g (35.5%) Id as an oil. IR (neat) 1730 cm⁻¹; NMR δ, 1.40 (s, 3, CH₃), 2.47 (s, 3, NCH₃), 3.84 (s, 3, OCH₃), 3.98(s, 4, OCH₂ CH₂ O), 6.7-7.2 (m, 3, ArH).

Anal. Calcd. for C₂₀ H₂₇ NO₄ : C, 69.54; H, 7.88; N, 4.05. Found: C,69.02; H, 7.63; N, 4.03.

EXAMPLE 31 ##STR77##2-N-Cyclopropylmethylamino-7-methoxy-3,4-dihydronaphthalene.

Into a 3-neck round-bottomed flask fitted with mechanical stirrer, asoxlet extractor packed with molecular sieves (50 g, type 3A), acondenser and a nitrogen inlet tube was added 10.75 g (100 mmol)cyclopropylmethylamine hydrochloride, 0.75 ml water (to solubilize thesalt) and 10.1 g (100 mmol) triethylamine. After stirring for 10-15 minto liberate the cyclopropylmethylamine, a solution of 12.30 g (70 mmol)of 7-methoxy-2-tetralone in 100 ml benzene was added and the mixture(under nitrogen) was refluxed with stirring for 5 hrs. After cooling toroom temperature, solids (triethylamine hydrochloride) were fastfiltered off and washed on the funnel with ether (50 ml). The combinedfiltrate and washings were evaporated to dryness to give 15.8 g (99%) ofXIIa as a pale yellow air-sensitive liquid; IR (neat), 3420 (NH), 1635cm⁻¹ (C═C--N); NMR δ, 0.15-1.15 (m, 5, cyclopropyl), 2.15 (m, benzylic),2.63-2.95 (m, 4, allylic and N--CH₂), 3.40 (broad, 1, NH), 3.75 (s, 3,OCH₃), 5.18 (s, 1, C-1H), 6.63-7.0 (m, 3, ArH).

Anal. Calcd. for C₁₅ H₁₉ NO: C, 78.57; H, 8.35; N, 6.11. Found: C,78.93; H, 8.41; N, 6.03.

EXAMPLE 32 ##STR78##2-N-Cyclobutylmethylamino-7-methoxy-3,4-dihydronaphthalene.

Employing the procedure of Example 31, 7-methoxy-2-tetralone (70.4 g,400 mmole) was reacted with cyclobutylmethylamine [generated in situfrom 62.7 g (516 mmole) of its hydrochloride by treatment with anequimolar amount of triethylamine and 4.0 ml of water] in benzene (300ml) to provide 93.40 g (96.5%) of XIIb as a pale yellow air-sensitivesyrup; IR (neat), 3420 (NH), 1635 cm⁻¹ (C═C--N); NMR δ, 3.70 (s, 3,OCH₃), 5.15 (s, 1, C-1H), 6.25-6.90 (m, 3, ArH).

Anal. Calcd. for C₁₆ H₂₁ NO: C, 78.97; H, 8.69; N, 5.75. Found: C,79.26; H, 8.73; N, 5.65.

EXAMPLE 33 ##STR79##7-Benzyloxy-2-N-cyclobutylmethylamino-3,4-dihydronaphthalene.

Employing the procedure of Example 31, 7-benzyloxy-2-tetralone (36.5 g,145 mmole) was reacted with cyclobutylmethylamine [generated in situfrom 22.7 g (187 mmole) of its hydrochloride by treatment with anequimolar amount of triethylamine and 1.5 ml water] in benzene (110 ml)and the product isolated to yield 46.28 g (99%) of XIIc as a paleyellow, air-sensitive syrup; IR (neat), 3420 (NH), 1635 cm⁻¹ (C═C--N);NMR δ, 4.98 (s, 2, ArCH₂ O), 5.15 (s, 1, C-1H), 6.35-7.40 (m, 8, ArH).

Anal. Calcd. for C₂₂ H₂₅ NO: C, 82.83; H, 7.89; N, 4.38. Found: C,82.87; H, 7.79; N, 4.23.

EXAMPLE 34 ##STR80## 2-Methylamino-7-methoxy-3,4-dihydronaphthalene.

This compound was prepared according to the procedure described byEvans, et al., J. Org. Chem. 35, 4122 (1970) as follows. Into a dry,nitrogen purged, 500 ml, 3-neck flask fitted with mechanical stirrer,dropping funnel and nitrogen inlet tube was added a solution of 14.3 g(460 mmole) methylamine in anhydrous ether (100 ml) and a solution of20.0 g (113.5 mmole) 7-methoxy-2-tetralone in same solvent (100 ml) andthe solution was placed under a slow stream of nitrogen and cooled to-18° (ice-methanol). A solution of 11.56 g (61 mmole) titaniumtetrachloride in pentane (50 ml) was added dropwise with stirring over30 min period. After the addition, the reaction mixture was stirred atroom temperature for 1 hr and then fast filtered. The solid residue waswashed with ether (50 ml) and the filtrate and washings were combined.Removal of the solvent in vacuo gave 20.6 g (96%) of XIId as anoxygen-sensitive oil which crystallized on standing; IR (neat), 3430(NH), 1630 cm⁻¹ (C═C--N); NMR δ, 2.15 (m, 2, benzylic), 2.55 (m, 2,allylic), 2.70 (s, 3, NCH₃), 3.15 (broad, NH), 3.70 (s, 3, OCH₃), 5.13(s, 1, C-1H), 6.25-6.90 (m, 3, ArH).

Anal. Calcd. for C₁₂ H₁₅ NO: C, 76.15; H, 7.99; N, 7.40. Found: C,75.44; H, 7.92; N, 7.19.

EXAMPLE 35 ##STR81##3-Cyclopropylmethyl-8-methoxy-1,2,4,5-tetrahydro-3H-benz[e]indole.

This compound was prepared according to the procedure described byEvans, et al., J. Org. Chem. 35, 4122 (1970) for the synthesis of3-methyl-1,2,4,5-tetrahydro-3H-benz[e]indole as follows. Into a dry,nitrogen filled, one liter 3-neck flask fitted with reflux condenser,serum cap, dropping funnel and magnetic stirrer, was added a solution of38.55 g (167.9 mmol) XIIa in dry tetrahydrofuran (THF) (50 ml) which wasplaced under a slow stream of nitrogen. A 2.20 M solution of isopropylmagnesium chloride in THF (96.1 ml, 211.7 mmol) was added slowly via asyringe at such a rate as to maintain gentle reflux. After the addition(15 min), 30.72 g (214.2 mmol) of bromochloroethan was added to the warmreaction mixture at a rate sufficient to maintain gentle refluxing.After the addition of the alkylhalide, an additional 52.3 ml (115 mmol)of the Grignard reagent was added to the reaction again at a controlledrate. The reaction mixture was cooled in an ice-bath and 270 ml of 1 Maqueous solution of ethylenediaminetetraacetic acid tetrasodium salt wasadded slowly (with stirring) and then 600 ml of a 1:1 ether-benzene wasadded. The organic layer was separated and the aqueous phase wasextracted with ether. The combined extracts were washed with water(2×100 ml) and dried (MgSO₄). Removal of the solvent by evaporation gave43.0 g (99%) of XIIIa as a pale yellow oxygen-sensitive oil; IR (neat),1635 cm⁻¹ (C═C--N).

Anal. Calcd. for C₁₇ H₂₁ NO: C, 79.96; H, 8.29; N, 5.48. Found: C,79.86; H, 8.35; N, 5.41.

EXAMPLE 36 ##STR82##3-Cyclobutylmethyl-8-methoxy-1,2,4,5-tetrahydro-1H-benz[e]indole.

Employing the procedure of Example 35, compound XIIb (93.4 g) wasconverted to XIIIb (98.0 g, 94.5%); pale brown oxygen-sensitive oil; IR(neat), 1635 cm⁻¹ (C═C--N).

Anal. Calcd. for C₁₈ H₂₃ NO: C, 80.25; H, 8.60; N, 5.19. Found: C,80.15; H, 8.71; N, 5.09.

EXAMPLE 37 ##STR83##8-Benzyloxy-3-cyclobutylmethyl-1,2,4,5-tetrahydro-1H-benz[e]indole.

Employing the procedure of Example 35, compound XIIc (46.0 g) wasconverted to XIIIc; yield 48.0 g (98%); IR (CHCl₃), 1635 cm⁻¹ (C═C--N).

Anal. Calcd. for C₂₄ H₂₆ NO: C, 83.43; H, 7.87; N, 4.06. Found: C,83.72; H, 7.77; N, 3.96.

EXAMPLE 38 ##STR84##3-Methyl-8-methoxy-1,2,4,5-tetrahydro-1H-benz[e]indole.

Employing the procedure of Example 35, compound XIId (19.0 g) wasconverted to XIIId, yield 20.6 g (96%); IR (neat), 1635 cm⁻¹ (C═C--N);NMR, 2.62 (s, 3, NCH₃), 3.75 (s, 3, OCH₃), 6.6-7.1 (m, 3, ArH). Thismaterial was used in Example 42.

A sample was converted to the picrate salt; m.p. 108.5°-110°.(acetone-ether).

Anal. Calcd. for C₂₀ H₂₁ N₄ O₈ : C, 53.93; H, 4.75; N, 12.58. Found: C,53.79; H, 4.65; N, 12.68.

EXAMPLE 39 ##STR85##9b-Allyl-3-cyclopropylmethyl-8-methoxy-5,9b-dihydrobenz[e]indoline (a)Preparation From3-cyclopropylmethyl-8-methoxy-1,2,4,5-tetrahydro-3H-benz[e]indole XIIIa.

A solution of 43.0 g (167.9 mmol) XIIIa and 25.0 g (206 mmol) of allylbromide in dry benzene (120 ml) was refluxed with stirring under anitrogen atmosphere for 10 hrs. An oily precipitate was formed. Aftercooling to room temperature, the supernatant liquor was decanted and theresidue was treated with acetone (50 ml) to provide a crystallineprecipitate which was filtered to give 36.3 g (57.5%) of XIVa (R₁=methyl, R₂ =allyl, R₃ =cyclopropylmethyl, X=Br), m.p. 160°-165°. Ananalytical sample was obtained by crystallization from acetone-ether,m.p. 172°-174°.

Anal. Calcd. for C₂₀ H₂₆ BrNO: C, 63.84; H, 6.94; Br, 21.24. Found: C,63.94; H, 6.94; Br, 21.13.

The yield of crystalline XIVa was 67% when acetonitrile was used as thesolvent in place of benzene in the above procedure.

Benz[e]indoline IIe was quantitatively obtained from the hydrobromideXIVa by treatment with 10% aqueous sodium hydroxide and extraction withether. IR (neat), 1670 cm⁻¹ (C═C--N); NMR δ, 3.77 (s, 3, OCH₃), 4.35(broad, 1, NC═CH), 4.75-5.91 (m, 3, olefinic), 6.5-7.1 (m, 3, ArH).

(b) Preparation From1-allyl-1-[2-(N-cyclopropylmethylamino)ethyl]-2,2-ethylenedioxy-7-methoxy-1,2,3,4-tetrahydronaphthalene(XIXa).

To a solution of 30.4 g (85 mmole) XIXa in ethanol (125 ml) was added asolution of 4% hydrochloric acid (125 ml). The reaction mixture wasstirred at room temperature overnight (16 hrs) and then concentratedunder vacuum to about half volume, alkalified with 10% sodium hydroxideand extracted with ether (2×100 ml). Combined extracts were washed withwater (2×80 ml) and dried (MgSO₄). Removal of the solvent under vacuumgave 23.0 g (92%) IIe identical with the material prepared in Example39(a) above.

EXAMPLE 40 ##STR86##9b-Allyl-3-cyclobutylmethyl-8-methoxy-5,9b-dihydrobenz[e]indoline (a)Preparation From3-cyclobutylmethyl-8-methoxy-1,2,4,5-tetrahydro-1H-benz[e]indole(XIIIb).

A solution of 18.0 g (67 mmol) XIIIb and 10.5 g (87 mmol) allyl bromidein dry acetonitrile (60 ml) was refluxed under a nitrogen atmosphere for16 hrs. After removal of the solvent in vacuo, the residue was treatedwith acetone (50 ml) and the crystalline product collected to give 15.5g (59%) of XIVb (R₁ =methyl, R₂ =allyl, R₃ =cyclobutylmethyl, X=Br),m.p. 168°-170°.

Anal. Calcd. for C₂₁ H₂₈ BrNO: C, 64.61; H, 7.23; Br, 20.47. Found: C,64.38; H, 7.25; Br, 20.35.

The yield of crystalline XIVb was 49% when benzene was used as thesolvent in place of acetonitrile in the above procedure.

The benz[e]indoline IIf was quantitatively obtained from thehydrobromide XIVb by treatment with sodium hydroxide and extraction withether; IR (neat), 1670 cm⁻¹ (C═C--N); NMR δ, 3.75 (s, 3, OCH₃), 4.36(broad, 1, NC═CH), 4.75-5.9 (m, 3, olefinic), 6.5-7.1 (m, 3, ArH).

(b) Preparation From1-allyl-1-[2-(N-cyclobutylmethylamino)ethyl]-2,2-ethylenedioxy-7-methoxy-1,2,3,4-tetrahydronaphthalene(XIXb).

Compound XIXb (33.7 g) treated with hydrochloric acid in aqueous ethanolaccording to Example 39(b) afforded 27.5 g (98%) IIf identical with thematerial obtained in Example 40(a) above.

EXAMPLE 41 ##STR87##9-Allyl-8-benzyloxy-3-cyclobutylmethyl-5,9b-dihydrobenz[e]indoline.

A mixture of 48.0 g (139 mmol) XIIIc and 21.9 g (181 mmol) allyl bromidein dry acetonitrile (140 ml) was refluxed under a nitrogen atmospherefor 16 hrs. After removal of the solvent by evaporation, the residue wastreated with acetone (150 ml) and crystalline material collected to give40.0 g (63%) of XIVc (R₁ =benzyl, R₂ =allyl, R₃ =cyclobutylmethyl,X=Br), m.p. 181.5°-183.5°. An analytical sample was obtained byrecrystallization from ethanol; m.p. 183°-184°.

Anal. Calcd. for C₂₇ H₃₂ BrNO: C, 69.52; H, 6.91; N, 3.00; Br, 17.13.Found: C, 69.56; H, 6.92; N, 2.90; Br, 16.96.

The enamine IIg was quantitatively obtained from the hydrobromide (XIVc)by treating with sodium hydroxide and extraction with ether; IR (neat),1760 cm⁻¹ (C═C--N): NMR δ, 4.40 (broad, 1, NC═CH), 5.07 (s, 2, ArCH₂ O),4.73-5.90 (m, 3, olefinic), 6.75-7.5 (m, 8, ArH).

EXAMPLE 42 ##STR88##9b-Allyl-8-methoxy-3-methyl-5,9b-dihydrobenz[e]indoline.

A solution of 5.04 g (23.4 mmol) XIIId and 3.70 g (30.5 mmol) allylbromide in dry acetonitrile (20 ml) was refluxed for 16 hr under anitrogen atmosphere. Removal of the solvent in vacuo left a stickyresidue of XIVd (R₁ =R₃ =methyl, R₂ =allyl, X=Br) which was purified byconversion to the picrate salt as follows. The hydrobromide XIVd (X=Br)was dissolved in water (100 ml) and extracted with ether (2×50 ml) toremove neutral material and these ethereal extracts were discharged. Theaqueous phase was made alkaline with 10% sodium hydroxide (30 ml) andextracted with ether (2×70 ml). The ethereal solution was washed withwater (3×30 ml), dried (MgSO₄) and the solvent removed in vacuo. Theliquid residue (5.1 g) was dissolved in ethanol (20 ml) and added to asolution of 6.8 g picric acid in hot ethanol (50 ml) and allowed tocrystallize at room temperature. The crystalline product was filtered togive 8.6 g (76%) of XIVd (X=picric acid), m.p. 143°-147°. An analyticalsample obtained by crystallization from ethanol-acetone (1:15); m.p.147°-148°, was identical with IIa prepared according to Example 17.

The yield of XIVd picrate was 66% when benzene was in place ofacetonitrile in the above procedure.

The benz[e]indoline IIa was regenerated from the picrate XIVd (X=picricacid) as follows: A mixture of finely powder picrate (10 mmol), 1 Naqueous lithium hydroxide (50 ml), ethanol (20 ml) and ether (100 ml) ina separatory funnel was shaken until all the picrate had dissolved. Theether phase was washed with water and, after drying, was evaporated todryness to give the free base IIa quantitatively.

EXAMPLE 43 ##STR89##9b-Benzyl-8-methoxy-3-methyl-5,9b-dihydrobenz[e]indoline.

A solution of 27.3 g (127 mmol) XIIId and 25.0 g (197 mmol) benzylchloride in 130 ml dry acetonitrile was refluxed under a nitrogenatmosphere for 18 hrs. Removal of the solvent in vacuo left a residueXIVe (R₁ =R₃ =methyl, R₂ =benzyl, X=Br) which resisted crystallization.The residue was dissolved in water (150 ml), extracted with ether (2×100ml) to remove neutral material and the ethereal extracts weredischarged. The aqueous phase was treated with 10% sodium bicarbonate(200 ml) and extracted with ether (3×100 ml). The combined etherealextracts were washed with water (2×100 ml), dried, and the solventremoved in vacuo to give 30 g (78%) of IIh as a light brown syrup. Thepurity of this material was approximately 90% as estimated by NMR.

The crude benz[e]indoline IIh was treated with picric acid according toExample 42 to give 28.5 g. (42% based on XIIId) of the picric salt XIVe(X=picric acid) m.p. 123°-126° (crystallized from ethanol-acetone, 1:4).

Anal. Calcd. for C₂₇ H₂₆ N₄ O₈ : C, 60.66; H, 4.90; N, 10.48. Found: C,59.99; H, 4.93; N, 10.52.

The benz[e]indoline IIh was quantitatively regenerated from the picrateby the procedure described in Example 42; IR (neat) 1670 cm⁻¹ (C═C--N);NMR δ, 2.65 (s, 3, NCH₃), 2.80 (s, 2, ArCH₂), 3.72 (s, 3, OCH₃), 4.37(dd, 1, NC═CH, J₁ =5.5, J₂ =2.5 Hz), 6.50-7.35 (m, 8, ArH).

The yield of crude IIh was 60% when dioxane was used as the reactionsolvent in place of acetonitrile in the above procedure and the yield ofthe picrate ws 39%.

The yield of crude IIh was 10% where benzene was used as the reactionsolvent in the above procedure.

EXAMPLE 44 ##STR90##1-Allyl-7-methoxy-2-oxo-1,2,3,4-tetrahydro-1-naphthaleneacetonitrile.

1-Allyl-3,4-dihydro-7-methoxy-2(1H)-naphthalenone (VIIIa) 256.5 g (1.186mole) in 250 ml dry dimethylformamide (DMF) was added dropwise to astirred, cold (ice-bath) suspension of 24.86 g (1.186 mole) sodiumhydride (or 49.92 g of 57% dispersion in oil washed with benzene) in 350ml DMF under nitrogen. After the addition, (1 hr), the reaction mixtureis stirred at room temperature for 2 hr and then cooled in an ice-bath.A solution of 89.54 g (1.186 mole) chloroacetonitrile in 300 ml dry DMFwas added in a period of 1 hr, then the cooling bath removed andstirring continued at room temperature overnight. Water (1500 ml) andether (300 ml) were added and on stirring a crystalline materialprecipitated. It was separated by filtration to give 210 g of XV. Theorganic phase in the filtrate was separated and the aqueous phase wasextracted with benzene (4×200 ml). Combined extracts were washed withwater (3×150 ml), dried and evaporated to dryness. The syrup residue wastriturated with ether (200 ml) and on cooling it crystallized to give anadditional 40.0 g product XV. The two crystalline crops were combined(250 g) and recrystallized from 1:1 ethanol-ether to give 231.0 g (76%)of compound XV, m.p. 90°-96°. A sample was distilled at 150°-160°/0.1 mmHg and the distillate was crystallized from EtOH-ether to give ananalytical sample, m.p. 94°-96°, IR (CHCl₃) 2250 (CN), 1715 cm⁻¹ (CO);NMR δ, 3.77 (s, 3, OCH₃), 4.75-5.65 (m, 3, CH--CH₂), 6.65-7.15 (m, 3,ArH).

Anal. Calcd. for C₁₆ H₁₇ NO₂ : C, 75.26; H, 6.71; N, 5.48. Found: C,74.85; H, 6.97; N, 5.54.

EXAMPLE 45 ##STR91##1-Allyl-2,2-ethylenedioxy-7-methoxy-1,2,3,4-tetrahydro-1-naphthaleneacetonitrile.

Into a round bottomed flask fitted with a Soxlet extractor packed withmolecular sieves-3A (80 g), condenser and magnetic stirrer was added71.5 g (0.2 mole) crude XV (m.p. 90°-96°), 90 ml ethyelene glycol, 1.0 gp-toluenesulfonic acid and 250 ml dry toluene and the mixture wasrefluxed with stirring. At intervals (8-10 hrs), the sieves werereplaced with fresh ones. After refluxing for 48 hrs the reactionmixture was cooled to room temperature and diluted with 10% NaHCO₃ (100ml). The organic phase was separated and the aqueous phase extractedwith benzene (2×50 ml). Combined extracts were washed with water anddried. Removal of the solvent by evaporation and trituration of theresidue with ethanol (60 ml) gave 64.0 g (76%) of compound XVI, m.p.82°-85°. A sample crystallized twice from the same solvent melted at85°-86°; IR (CHCl₃), 2250, 1615, 1505; NMR δ, 3.75 (s, 3, OCH₃), 4.06(s, 4, OCH₂ CH₂ O), 4.85-6.0 (m, 3, olefinic), 6.6-7.15 (m, 3, ArH).

Anal. Calcd. for C₁₈ H₂₁ NO₃ : C, 72.21; H, 7.07; N, 4.68. Found: C,72.23; H, 7.10; N, 4.50.

EXAMPLE 46 ##STR92##1-Allyl-2,2-ethylenedioxy-7-methoxy-1-(2-aminoethyl)-1,2,3,4-tetrahydronaphthalene.

A solution of 33.2 g (0.111 mole) of XVI in 480 ml dry ether was addeddropwise under nitrogen and stirring to a suspension of 8.43 g (0.22mole) lithium aluminum hydride in 210 ml dry ether. After the addition,(30 min), stirring at room temperature was continued for 48 hrs. Thereaction mixture was cooled in an ice bath and excess hydride and thecomplex decomposed by dropwise addition, successively of 8.5 ml water,6.4 ml 20% sodium hydroxide and 29.5 ml water. The granular inorganicprecipitate thus obtained was filtered and rinshed with ether (100 ml)and the resulting ether solution dried (MgSO₄). Removal of the solventin vacuo afforded 33.5 g (100%) of syrup XVII. The IR spectrum of thereduction production ans TLC (alumina, CH₂ Cl₂) affirmed the absence ofany unreduced nitrile. A sample was purified by chromatography on analuminum oxide column eluted first with methylene chloride to remove theimpurities and then with ethanol to extract the product; NMR δ, 1.05 (s,2, NH₂), 3.70 (s, 3, OCH₃), 3.91 (s, 4, OCH₂ CH₂ O), 4.73-6.0 (m, 3,olefinic), 6.5-7.0 (m, 3, ArH).

Anal. Calcd. for C₁₈ H₂₅ NO₃ : C, 71.25; H, 8.30; N, 4.61. Found: C,70.74; H, 8.35; N, 4.50.

EXAMPLE 47 ##STR93##1-Allyl-1-(2-cyclopropanecarboxamidoethyl)-2,2-ethylenedioxy-7-methoxy-1,2,3,4-tetrahydronaphthalene.

To an ice cold solution of 10.8 g (35.7 mmol) of crude XVII and 8.3 ml(60 mmole) triethylamine in 25 ml methylene chloride was added dropwisewith stirring a solution of 4.18 g (40 mmol) cyclopropanecarbonylchloride in 15 ml methylene chloride. After stirring for 1 hr in thecold and 2 hr at room temperature, it was washed with water and 10%sodiumbicarbonate and dried (Na₂ SO₄). Removal of the solvent byevaporation and trituration of residue with ether (50 ml) gave 10.5 g(79.5%) crystalline XVIIIa, m.p. 94°-95°, solidified and remelted at114°-115°. The m.p. was unchanged when a sample recrystallized from 1:1ethanolether; IR (CHCl₃), 3320 (NH), 1650 and 1555 cm⁻¹ (CO). NMR δ,0.3-0.8 (m, 5, ##STR94## 3.75 (s, 3, OCH₃), 4.0 (s, 4, OCH₂ CH₂ O),4.75-6.0 (m, 3, olefinic), 6.50-7.10 (m, 3, ArH).

Anal. Calcd. for C₂₂ H₂₉ NO₄ : C, 71.13; H, 7.87; N, 3.77. Found: C,71.10, H, 8.03; N, 3.67.

EXAMPLE 48 ##STR95##1-Allyl-1-(2-cyclobutanecarboxamidoethyl)-2,2-ethylenedioxy-7-methoxy-1,2,3,4-tetrahydronaphthalene.

Reaction of XVII with cyclobutanecarbonyl chloride as describedaccording to the procedure of Example 47 provided an 83% yield ofXVIIIb, m.p. 99°-101° (crystallized from benzene-ligroin); NMR δ, 3.81(s, 3, OCH₃), 4.06 (s, 4, OCH₂ CH₂ O), 4.86-6.05 (m, 3, olefinic),6.6-7.1 (m. 3, ArH).

Anal. Calcd. for C₂₃ H₃₁ NO₄ : C, 71.66; H, 8.10; N, 3.63. Found: C,71.60; H, 8.21; N, 3.32.

EXAMPLE 49 ##STR96##1-Allyl-1-[2-(N-cyclopropylmethylamino)ethyl]-2,2-ethylenedioxy-7-methoxy-1,2,3,4-tetrahydronaphthalene.

To a suspension of 3.0 g (81 mmol) lithium aluminum hydroxide in dryether (160 ml) was added dropwise with stirring a solution of 14.8 g (40mmol) XVIIIa in dry THF (160 ml) at a rate to maintain gentle refluxing.After stirring at room temperature for 48 hrs, the reaction mixture wascooled in an ice-bath and the excess of hydride and the complex weredecomposed by the successive dropwise addition of water (3.0 ml) 20%sodium hydroxide (2.25 ml) and water (10.5 ml). The inorganicprecipitate was filtered and rinsed with ether (50 ml). The combinedfiltrate and washings, after drying (MgSO₄) were evaporated to drynessto give 14.0 g (98%) of XIXa as a syrup; NMR δ, 3.71 (s, 3, OCH₃), 3.95(s, 4, OCH₂ CH₂ O), 4.7-6.0 (m, 3, olefinic), 6.5-7.0 (m, 3, ArH).

Anal. Calcd. for C₂₂ H₃₁ NO₃ : C, 73.91; H, 8.74; N, 3.91. Found: C,73.38; H, 8.89; N, 3.76.

EXAMPLE 50 ##STR97##1-Allyl-1-[2-(N-cyclobutylmethylamino)ethyl]-2,2-ethylenedioxy-7-methoxy-1,2,3,4-tetrahydronaphthalene.

Compound XIXb was obtained in 95% yield by reduction of XVIIIb accordingto the procedure of Example 49; NMR δ, 3,76 (s, 3, OCH₃), 4.0 (s, 4,OCH₂ CH₂ O), 4.8-6.0 (m, 3, olefinic), 6.60-7.10 (m, 3, ArH).

Anal. Calcd. for C₂₃ H₃₃ NO₃ : C, 74.35; H, 8.95; N, 3.77. Found: C,74.36; H, 9.13; N, 3.56.

EXAMPLE 51 ##STR98##9b-Allyl-4-bromo-8-methoxy-2,4,5,9b-tetrahydro-1H-benz[e]indolecyclopropylmethobromide.

To a solution of 11.9 g (74.5 mmol) bromine in 750 ml methylene chloridepreviously cooled in an acetone-dry ice bath under nitrogen and stirringwas added all at once a solution of 22.06 g (74.5 mmol) of the enamineIIe in 50 ml methylene chloride. After stirring at the above temperaturefor 5 min and at room temperature for 20 min, the solvent was removed invacuo leaving a solid residue which was triturated with ether (100 ml)and filtered to give 33.0 g (98.5%) of pale yellow color crystallineproduct IIIe, m.p. 112°-117°; IR (nujol) 1670 cm⁻¹.

Anal. Calcd. for C₂₀ H₂₅ Br₂ NO: C, 52.76; H, 5.53; Br, 35.10. Found: C,52.65; H, 5.48; Br, 34.96.

A sample recrystallized from ethanol melted at 133°-134°.

Anal. Found: C, 52.68; H, 5.79; Br, 35.05.

EXAMPLE 52 ##STR99##9b-Allyl-4-bromo-8-methoxy-2,4,5,9b-tetrahydro-1H-benz[e]indolecyclobutylmethobromide.

The enamine IIf (10.0 g, 32.4 mmol) was brominated by the procedure ofExample 51. After removal of the solvent in vacuo, the residue wasdissolved in acetone (25 ml) and diluted with ether (50 ml). The paleyellow crystalline product was filtered to give 13.8 g (91%) of IIIf,m.p. 117°-120°.

Anal. Calcd. for C₂₁ H₂₆ Br₂ NO: C, 53.86; H, 5.59; Br, 34.12; N, 2.99.Found: C, 53.88; H, 5.85; Br, 34.24; N, 2.86.

EXAMPLE 53 ##STR100##9b-Allyl-8-benzyloxy-4-bromo-2,4,5,9b-tetrahydro-1H-benz[e]indolecyclobutylmethobromide.

The enamine IIg (30.1 g, 78.2 mmol) was brominated by the procedure ofExample 51. After removal of the solvent in vacuo, the solid residue wastriturated with acetone (100 ml) and filtered to give 30.0 g (73%) ofIIIg, m.p. 109°-112°. A sample crystallized twice from ethanol-ethermelted at 114°-115°.

Anal. Calcd. for C₂₇ H₃₁ Br₂ NO: C, 59.46; H, 5.72; Br, 29.30; N, 2.56.Found: C, 59.64; H, 5.88; Br, 29.12; N, 2.57.

EXAMPLE 54 ##STR101##9b-Benzyl-4-bromo-8-methoxy-2,4,5,9b-tetrahydro-1H-benz[e]indolemethobromide.

The enamine IIh (14.0 g, 46.8 mmol) was brominated by the procedure ofExample 51. Removal of the solvent in vacuo and trituration of theresidue with acetone (50 ml) gave 17.2 g (82%) of pale yellow crytallineIIIh, m.p. 103°-106°.

Anal. Calcd. for C₂₁ H₂₃ Br₂ NO: C, 54.21; H, 4.98; Br, 34.35. Found: C,54.46; H, 5.01; Br, 34.08.

EXAMPLE 55 ##STR102##5-Allyl-2-cyclopropylmethyl-2'-methoxy-9-oxo-6,7-benzomorphan Method A.From IIIe by treatment with ammonium bicarbonate.

To a solution of 9.1 g (20 mmol) IIIe in 95% ethanol (170 ml),previously cooled in an ice-salt bath under nitrogen and stirring, wasadded dropwise in 1.5 hr period a solution of 1.70 g (21.5 mmol)ammonium bicarbonate in water (21 ml). Oily bromoenamine IVe (R₁=methyl, R₂ =cyclopropylmethyl, R₃ =allyl) had deposited on the sides ofthe flask. After the addition of the bicarbonate, the reaction mixturewas stirred in cold for 2 hrs and at room temperature for 48 hrs. It wasconcentrated under reduced pressure to a small volume, the residue wastreated with 10% sodium bicarbonate (50 ml) and extracted with ether(3×50 ml). The combined ethereal extracts were washed with water (3×30ml), dried (MgSO₄) and the solvent removed in vacuo to give 4.6 g ofcrude Ie. TLC on alumina with ether showed one major spot with Rf 0.78(Ie) and a minor one with Rf 0. The syrup was dissolved in dry-acetone(10 ml), added to a solution of 2.0 g anhydrous oxalic acid in acetone(10 ml) and the resulting solution was diluted with dryether (10 ml).The crystalline product was filtered to give 4.0 g (50%) of the oxalateof Ie, m.p. 148.5°-150.0°.

Anal. Calcd. for C₂₂ H₂₇ NO₆ : C, 65.82;H, 6.78; N, 3.48. Found: C,65.57; H, 7.08; N, 3.40.

The free base Ie was regenerated quantitatively from the oxalate (sodiumhydroxide-ether); IR (neat) 1730 cm⁻¹ ; NMR δ, 3.75 (s, 3, OCH₃),4.85-6.15 (m, 3, olefinic).

Method B. From IIIe by treatment with aluminum oxide.

A mixture of 5.0 g (11 mmol) of IIIe and 25 g aluminum oxide G (type Efor thin layer chromatography, Merck, Germany) in 50 ml of 75%dimethylsulfoxide-water was stirred under nitrogen for 24 hrs. Thereaction mixture was filtered and the filter-cake washed with ethanol(2×25 ml) and water (2×20 ml). The filtrate and washings were combined,diluted with water (150 ml) and 10% sodium bicarbonate (50 ml) andextracted with ether (3×50 ml). After drying, the solvent was removed byevaporation and the liquid residue (2.70 g) was converted to theoxalate, to give 2.6 g (59%) of Ie oxalate, m.p. 148°-150°.

EXAMPLE 56 ##STR103##5-Allyl-2-cyclobutylmethyl-2'-methoxy-9-oxo-6,7-benzomorphan.

The bromoenaminium bromide IIIf (46.9 g) was treated with ammoniumbicarbonate by the procedure of Example 55. In the initial stages of thereaction, the bromoenamine IVf (R₁ =methyl, R₂ =allyl, R₃=cyclobutylmethyl) deposited on the sides of the flask and dissolved asthe reactions progressed. The crude If was chromatographed on a columnof aluminum oxide (22.5 cm long×6.5 cm I.D.) with methylene chloride andthe portion containing If was evaporated to give 20.0 g (61.5%) syrup.The syrup, dissolved in dry acetone (60 ml), was added to a solution of10.0 g anhydrous oxalic acid in dry acetone (50 ml) and diluted with dryether (50 ml) to give 20.0 g (48%) of the oxalate of If, m.p. 176°-179°.The oxalate (slightly colored) was stirred with boiling acetone (100 ml)and after cooling, filtered to give 19.5 g, m.p. 182°-182.5°.

Anal. Calcd. for C₂₃ H₂₉ NO₆ : C, 66.48; H, 7.03; N, 3.37. Found: C,66.72; H, 6.99; N, 3.30.

The free base If was regenerated from the oxalate by treatment withsodium hydroxide and extraction with ether; IR (neat) 1730 cm⁻¹ ; NMR δ,3.75 (s, 3, OCH₃), 4.85-6.15 (m, 3, olefinic).

EXAMPLE 57 ##STR104##5-Allyl-2'-benzyloxy-2-cyclobutylmethyl-9-oxo-6,7-benzomorphan.

A mixture of 5.45 g (10 mmol) IIIg and 25.0 g aluminum oxide in 75%dimethylsulfoxide-water (113 ml) was stirred at room temperature undernitrogen for 72 hrs. The reaction mixture was filtered and thefilter-cake was washed with ethanol (2×15 ml) and water (2×20 ml). Thecombined filtrate and washings were diluted with water (250 ml) and 10%sodium bicarbonate (50 ml) and extracted with ether (5×60 ml). Theethereal extract was washed with water (3×60 ml), dried (MgSO₄) anddecolorized with alumina (5.0 g). Removal of the solvent in vacuo left3.0 g syrup Ig. The syrup was dissolved in dry acetone (10 ml), mixedwith a hot solution of 1.2 g anhydrous oxolic acid in dry acetone (20ml) and diluted with dry ether (30 ml). The crystalline product wasfiltered to give 2.5 g (51%) of the oxalate of Ig, m.p. 165°-167°.

The free base Ig was regenerated from the oxalate by treatment withsodium hydroxide and extraction with ether; IR (neat) 1730 cm⁻¹ ; NMR δ,5.05 (s, 2, ArCH₂ O), 5.85-6.15 (m, 3, olefinic), 6.85-7.50 (m, 8, ArH).

The hydrobromide of Ig had m.p. 198°-199° (ethanol-ether).

Anal. Calcd. for C₂₇ H₃₁ NO₂.HBr: C, 67.21; H, 6.68; N, 2.90. Found: C,67.07; H, 6.83; N, 3.01.

EXAMPLE 58 ##STR105##5-Benzyl-2'-methoxy-2-methyl-9-oxo-6,7-benzomorphan. Method A. From IIIhby treatment with ammonium bicarbonate.

Following the procedure of Example 55 (Method A), 6.97 g (15 mmol) ofIIIh in 150 ml 95% ethanol was treated with 1 M solution of ammoniumbicarbonate (16.2 ml) and the reaction mixture stirred at roomtemperature for 72 hrs. In the initial stages of the reaction, thebromoenamine precipitated out of the solution as a yellow crystallineproduct and slowly dissolved as the reaction progressed. The compound Ihwas isolated and purified via the oxalate (21% yield), m.p. 150°-160°.

Method B. From IIIh by treatment with aluminum oxide.

A mixture of 4.65 g (10 mmol) IIIh and 23 g activated aluminum oxide in85% dimethylsulfoxide-water (90 ml) was stirred under nitrogen for 24hrs. The product was isolated and purified by chromatography on AluminaAct. II with 1% ethanol-methylene chloride, to yield 0.51 g (15.4%) Ih,m.p. 136.5°-137.5° (ethanol); IR (CHCl₃) 1730 cm⁻¹ ; NMR δ, 2.40 (s, 3,NCH₃), 3.35 (s, 2, ArCH₂), 3.65 (s, 3, OCH₃), 6.6-7.2 (m, 3, ArH).

Anal. Calcd. for C₂₁ H₂₃ NO₂ : C, 78.47; H, 7.21; N, 4.36. Found: C,78.42; H, 7.28; N, 4.30

What is claimed is:
 1. A process for preparing2'-alkoxy-2,5-di-substituted-9-oxo-6,7-benzomorphan compounds of formulaI ##STR106## wherein R₁ is lower alkyl of 1 to 4 carbon atoms inclusiveor benzyl;R₂ is lower alkyl of 1 to 4 carbon atoms inclusive, allyl,benzyl, or ##STR107## R₃ is lower alkyl of 1 to 4 carbon atomsinclusive, ##STR108## in which R₄ is hydrogen or methyl; which comprisessequential steps of, (a) brominating a dihydroben[e]indoline of formulaII ##STR109## in which R₁, R₂, and R₃ are as recited above wherein saidbromination is carried out by combining a methylene chloride solution ofthe formula II compound and a solution of bromine in methylene chlorideat a temperature in the range of -40° to -70° to produce abromoenaminium bromide compound have formula III ##STR110## in which R₁,R₂, and R₃ are as recited above; (b) treating the formula III compoundwith a bicarbonate base selected from the group consisting of potassiumbicarbonate, sodium bicarbonate, and ammonium bicarbonate for activatedaluminum oxide to produce the 9-oxo-6,7-benzomorphan compound of formulaI.
 2. The process of claim 1 wherein the formula II compound employed isthat wherein R₁ and R₃ are methyl and R₂ is allyl.
 3. The process ofclaim 1 wherein the formula II compound employed is that wherein R₁, R₂and R₃ are methyl.
 4. The process of claim 1 wherein the formula IIcompound employed is that wherein R₁ is benzyl, R₂ is allyl, and R₃ ismethyl.
 5. The process of claim 1 wherein the formula II compoundemployed is that wherein R₁ and R₃ are methyl and R₂ is(3-ethylenedioxy)butyl.
 6. The process of claim 1 wherein the formula IIcompound employed is that wherein R₁ is methyl, R₂ is allyl and R₃ iscyclopropylmethyl.
 7. The process of claim 1 wherein the formula IIcompound employed is that wherein R₁ is methyl, R₂ is allyl and R₃ iscyclobutylmethyl.
 8. The process of claim 1 wherein the formula IIcompound employed is that wherein R₁ is benzyl, R₂ is allyl, and R₃ iscyclobutylmethyl.
 9. The process of claim 1 wherein the formula IIcompound employed is that wherein R₁ and R₃ are methyl and R₂ is benzyl.10. The process of claim 1 wherein in step (a), the bromination reactionis carried out at a temperature of -40° to -70° for a period of 5-15minutes and then at room temperature for 15-30 minutes.
 11. The processof claim 1 wherein in step (a), the bromination reaction is carried outat a temperature of -60° for a period of 5-15 minutes and completed atroom temperature in 15-30 minutes.
 12. The process of claim 1 wherein instep (b), an ethanolic solution of the formula III compound and anaqueous solution of one molecular equivalent of a bicarbonate baseselected from the group consisting of sodium bicarbonate, potassiumbicarbonate, and ammonium bicarbonate are combined dropwise in a periodof 1-2 hours at a temperature of -5° to -15°, followed by stirring thereaction mixture at -5° to -15° for a period of 1-3 hours and then atroom temperature for a period of 20-28 hours.
 13. The process of claim 1wherein the step (b), the formula III compound is treated with activatedaluminum oxide in aqueous dimethylsulfoxide.